Novel phytic citrate compounds and process for preparing the same

ABSTRACT

The present invention provides a chemical compound or a salt thereof having the chemical formula of: 
     
       
         
         
             
             
         
       
     
     wherein said R is H or citrate and wherein at least one R is citrate. The salt of the chemical compound is the Na + , K + , Mg 2+ , or Ca 2+  salt of said chemical compound. The chemical compound is a chelator which chelates sodium, potassium or lithium, magnesium, calcium, copper, iron, lead, zinc, aluminum, mercury, cadmium, or chromium. It is also be used as an artery plaque dissolver and/or to treat age-related degenerative disorders, such as Alzheimer&#39;s disease. The present invention also provides a method for producing the phytic citrate compound and/or its salt.

RELATED APPLICATION

This is a continuation-in-part application which claims the priority ofU.S. patent application Ser. No. 10/894,919, filed on Jul. 19, 2004,which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a group of chemical compounds(hereinafter “phytic citrate compounds”) and/or their salts thereofhaving the chemical formula of:

wherein R is H or citrate and wherein at least one R is a citrate. Thesalts of the phytic citrate compounds include the Na⁺, K⁺, Mg²⁺, and/orCa²⁺ salts of the phytic citrate compounds. The phytic citrate compoundsare excellent metal chelators which chelate sodium, potassium orlithium, magnesium, calcium, copper, iron, lead, zinc, aluminum,mercury, cadmium, or chromium efficiently. They are also good arteryplaque dissolvers and can be used to treat age-related degenerativedisorders, such as Alzheimer's disease. The present invention alsoprovides a method for producing the phytic citrate compounds and/ortheir salts.

BACKGROUND OF THE INVENTION

Chelators are small molecules that bind very tightly to metal ions. Somechelators are simple molecules that are easily manufactured (e.g.,ethylenediaminetetraacetic acid [EDTA]). Others are complex proteinsmade by living organisms (e.g., transferrin). The key property shared byall chelators is that the metal ion bound to the chelator is chemicallyinert. Consequently, one of the important roles of chelators is todetoxify metal ions and prevent poisoning. For instance,ethylendiaminetetraacetic acid (EDTA) is used to treat patients withextreme, life-threatening hypercalcaemia, while the iron chelator,desferrioxamine, is used to remove excess iron that accumulates withchronic blood transfusions. Although many different types of chelatorsexist, only a few are clinically useful since most have dangerous sideeffects. EDTA has long been thought of as a significant chelating agent.However, there has been known toxicological implications of EDTA whensignificant quantities and concentrations enter the vascular system.(See U.S. Pat. Nos. 5,114,974 and 6,114,387).

Meanwhile, phytic acid in the medical community has been known as analternative to EDTA as a chelating agent. Phytic acid is a component ofevery plant seed and is found in a number of cereals and seeds. Althoughit is very soluble in water, alcohol (95% by volume) and acetone, it isonly relatively soluble in aqueous propylene glycol and aqueousglycerol, and practically insoluble in ether, benzene and hexane.Aqueous solutions of phytic acid are intensely acidic: pH 0.9 at 66grams/liter. Although phytic acid is a stable bioactive ingredient andfree radical inhibitor with metal chelation abilities with strongbuffering and anti-oxidant properties, it cannot be utilized as aproprietary flagship product.

In the invention to be presented below, a group of novel chemicalcompounds (hereinafter “phytic citrate compounds”) will be introduced.These novel compounds have at least one citrate molecule attached at thehydroxyl group of the citric acid to the phosphate of the phytatemolecule. The novel compounds demonstrate superior chelating effect thanEDTA and have the advantages to be used in humans due to theirbiodegradable and non-toxic properties.

SUMMARY OF THE INVENTION

The present invention provides a group of novel chemical compounds(“phytic citrate compounds”) and/or their respective salts. These novelchemical compounds are represented by the following formula:

wherein R is H, or citrate; and wherein at least one R is citrate. Thus,the above identified compounds include phytic mono-citrate, phyticdi-citrate, phytic tri-citrate, phytic tetra-citrate, phyticpenta-citrate, and phytic hexa-citrate. The most preferable compound isphytic hexa-citrate. The salts of the respective phytic citratecompounds include Na⁺, K⁺, Mg²⁺, or Ca²⁺ salts of the compounds. Themost favorable salts are the Ca²⁺, Mg²⁺, and Ca²⁺Mg²⁺ salts of thecompounds.

The phytic citrate compounds are each in a crystalline form, preferablyin a crystalline powder form. Additionally, the phytic citrate compoundsare soluable in aqueous solution, preferably in water solution.

The phytic citrate compounds are effective metal chelators, which arecapable of chelating mono-, bi-, and tri-valent ions, such as sodium,potassium or lithium, magnesium, calcium, copper, iron, lead, zinc,aluminum, mercury, cadmium, and/or chromium.

The phytic citrate compounds also have therapeutic effects on dissolvingartery plaque and/or for treating age-related degenerative disease, suchas Alzheimer's disease.

The present invention also provides a pharmaceutical composition whichcontains the phytic citrate compound or the salt thereof and apharmaceutically acceptable carrier.

The present invention also provides a method for producing the phyticcitrate compounds. The method includes the following steps: (1)dissolving a salt of phytic acid in an aqueous solution; (2) adding andstirring citric acid and/or citrate to the dissolved salt of phytic acidto form a citrated phytate solution; and (3) crystallizing the citratedphytate solution to form the phytic citrate compound and/or the saltthereof.

Based on the various quantities of Na-Phytate and citric acid/citrateused in the reaction, phytic mono-citrate, phytic di-citrate, phytictri-citrate, phytic tetra-citrate, phytic penta-citrate, and phytichexa-citrate is produced. For example, Na-phytate and citric acid (orcitrate) in the molar ratio of about 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6,respectively, could produce phytic mono-citrate, phytic di-citrate,phytic tri-citrate, phytic tetra-citrate, phytic penta-citrate, andphytic hexa-citrate, respectively.

The salt of phytic acid used in the production of the phytic citratecompound includes sodium phytate, potassium phytate, magnesium phytate,calcium phytate, and/or calcium magnesium phytate. The salt of thephytic acid is preferably dissolved in water. The dissolved citratedphytate solution is preferably to be heated, but up to less than 100° C.The phytic citrate compounds can be crystallized by any conventionaldrying method, preferably under 40° C., and most favorably under 110C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution rate of the phytic citrate compound (phytichexa-citrate) of the present invention (), as compared to those ofphytic acid (▪), and EDTA (♦). The results demonstrate that phyticcitrate exhibits superior dissolution capability to phytic acid andEDTA.

FIG. 2 shows the Re-dissolution rate of Fe²⁺ of the phytic citratecompound (phytic hexa-citrate) of the present invention (), as comparedto those of phytic acid (▪), and EDTA (♦). The results demonstrate thatphytic citrate exhibits superior redissolution capability to phytic acidand EDTA.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a group of new chemical compounds knownas the phytic citrate compounds and/or the salts of these compounds. Thepresent invention also provides a method for producing these compoundsand/or their salts. The phytic citrate compounds attach one to sixmolecules of citrate to a single phytate molecule by converting thethree carboxyl branches of the citric acid into three hydroxyl groups,thus, making the new compounds water soluble, due to the existence ofthe hydrophilic hydroxyl groups.

In the phytic citrate compounds, citric acid has been converted to acitrate with three hydroxyl groups per molecule. Each of the six carbonsof the citrate has an oxygen atom bound to the citrate molecule and thethree hydroxyl groups are connected to each carbon atom of the citratemolecule. Due to the chemical structures of these new compounds,particularly the large polar molecule with numerous hydroxyl groups,these compounds possess high solubility and chelation properties. Thesenew phytic citrate compounds have one to six citrate molecules attachedat the hydroxyl group of the citric acid to the phosphates of thephytate molecule. The resulting phytic citrate compounds have thefollowing generic formula:

where R is H or citrate and where at least one R is citrate.

The following examples illustrate the methods for making the phyticcitrate compounds and the characteristics of the phytic citratecompounds. These examples, however, are for illustrative purposes. Theyshould not be viewed as limitations of the scope of the presentinvention. Reasonable variations, such as those that occur to areasonable artisan, can be made herein without departing from the scopeof the present invention.

Example 1 Method for Preparation of the Phytic Citrate Compounds

Sodium Phytate was available commercially. The phytic citrate compoundswere made by dissolving sodium phytate in water. If necessary, heat andreflux could be used to facilitate the dissolution of sodium phytate. Itwas preferred that the heating of the solution was controlled to no morethan 100° C. and no more than 30 minutes. An adequate amount of citricacid or sodium citrate was then added to the dissolved phytate solution.The mixture was thoroughly stirred and then was sat for no more than 40°C., preferably in refrigerating environment (i.e., about 4-10° C.), forapproximately 6-8 hours to allow the newly formed phytic citratecompounds to crystallize or until the crystallization ceased. The phyticcitrate compounds were dried under room temperature by any conventionalmethods, including, but not limited to, vacuum drying, freeze-drying, ordrying at room temperature. Based on the quantities of the citricacid/citrate added, phytic mono-citrate, phytic di-citrate, phytictri-citrate, phytic tetra-citrate, phytic penta-citrate, and phytichexa-citrate, were produced. For example, Na-phytate and citric acid (orcitrate) in the molar ratio of about 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6,respectively, could produce phytic mono-citrate, phytic di-citrate,phytic tri-citrate, phytic tetra-citrate, phytic penta-citrate, andphytic hexa-citrate, respectively.

Example 2 Method for Preparation of Phytic Hexa-Citrate

Alternatively, the phytic hexa-citrate compound was produced by thefollowing method:

First, 0.33 kg of calcium carbonate was slowly added, in increments of0.1 kg, to 0.87 kg of phytic acid liquid. The mixture was heated andrefluxed for about one hour at about 90° C. The two solids wereseparated and filtered. The white solid, which was calcium phytate, wascollected. About 1 kg of the calcium phytate was dissolved into 2.0liters of water and heated to about 89° C. for about 10-15 minutes untilcalcium phytate was completely dissolved in the water solution. About0.9 kg of citric acid was then added to and stirred in the calciumphytate solution until the citric acid was completely dissolved. Theheat source was removed and the resulting mixture was left sat at nomore than 40° C. or in a refrigerated environment at a temperature ofabout 5-10° C. to allow the newly formed phytic hexa-citrate tocrystallize for approximately 6 to 8 hours or until crystallization hasceased. The mixture was allowed to dry out at room temperature until noliquid was visible. The crystals were spread in a drying pan forapproximately 24 hours at a temperature of no more than 40° C., whichyielded approximately 1.2 kg of hexa-citrated phytate.

Example 3 Chelating Effects of the Phytic Citrate Compounds

As shown below in Table 1 and in FIGS. 1-2, the phytic citrate compoundswere very effective oral chelators, which could maintain metals andmetalloids in the saline solution of blood. The new chemical compoundswere also very effective in dissolving artery plaque, as well asremoving excess copper, zinc, aluminum and iron in brain tissue, thus,providing a therapeutic means to treat patients with Alzheimer'sdisease, which is known to be caused by accumulation of metals in thepatients' brain tissues.

Chelation is a term which refers to the maintenance of soluble(dissolved) state of an ion, atom, or molecule. A chelator is anadditive which can redissolve a solid material which has been suspendedor has settled in a solution as a solid (precipitate). A strong chelatorhas the ability not only to dissolve the solid precipitates but also topowerfully maintain the dissolved state of particular solids. Chelatorsare used in industrial applications to prevent heavy metal fromprecipitating or falling out from solutions. There are many industrialchelators available commercially for various applications of watertreatment or to maintain ingredients of a solution to stay dissolvedindefinitely. The mechanism by which a chelator maintains the solubilityof what would otherwise be a solid is as follows: the chelator surroundsthe atom, ion or molecule which normally cannot dissolve in water. Thechelator then attaches to the solid at its hydrophobic end. The chelatormolecules then, once completely surrounding the solid, now create anexterior shell of the hydrophilic end of the chelator enabling the solidmolecule to dissolve completely in the solution even where it beforewould have existed as a precipitated solid.

Phytic acid is a very strong chelator of bivalent and trivalent heavymetals such as mercury, cadmium, chromium, iron, lead and aluminum.Citric acid on the other hand is a very effective chelator for amonovalent ion, such as sodium, potassium and lithium. Afterconsideration of many different nutritional supplements and bulk foodcommodities, it was discovered after countless experiments and computermodeling that the molecular structure of citric acid could be combinedwith phytic acid to form the new compounds possessing most of thebeneficial qualities of phytic acid and citric acid, which have beennamed the phytic citrate compounds. These include phytic mono-citrate,phytic di-citrate, phytic tri-citrate, phytic tetra-citrate, phyticpenta-citrate, and/or phytic hexa-citrate. Among these compounds,hexa-citrated phytate has the best chelating effect. The superiorchelating effect of hexa-citrated phytate, as opposed to other knownchelators, such as EDTA, acetic acid, lactic acid, citric acid, gluconicacid, and polyphosphoric acid, is demonstrated in the following Table:

TABLE 1 COMPARISON OF CHELATING EFFECTS Mg²⁺ Ca²⁺ Cu²⁺ Fe²⁺ Zn²⁺ (conc.of ions chelated) Phytic citrate 11.56 12.24 12.11 20.44 21.01 Phyticacid (pH 3) 9.56 9.73 10.41 16.84 15.50 Phytic acid (pH 5) 10.77 10.5510.85 17.35 14.96 Phytic acid (pH 7) 11.24 10.57 EDTA 8.69 10.70 18.8017.35 16.50 Acetic acid 0.51 0.53 1.03 Lactic acid 0.93 1.07 3.02 6.401.86 Citric acid 2.80 3.50 6.10 11.85 4.50 Gluconic acid 0.70 1.20 1.70Polyphosphoric acid 3.20 3.0 3.5 2.00 acid

The chelating effects of the various chelators were measured by theconventional method known to an artisan in the art. The concentration ofthe ions chelated by the chelator was determined using a divalent cationelectrode (e.g., Model 93-32, made by Orion Research Incorporated) andan ion analyzer (e.g., Model EA 920, made by Orion ResearchIncorporated).

The results of Table 1 demonstrate that phytic citrate has superiorchelating effects to other chelators.

FIG. 1 shows the dissolution rate (Kd) of phytic citrate (FIG. 1), ascompared to those of phytic acid and EDTA. The results demonstrate thatphytic acid has superior dissolution capability to other chelators indissolving plaques in the artery.

FIG. 2 shows the re-dissolution rate of Fe²⁺ (in brain tissues) amongphytic citrate, phytic acid and EDTA. The superior ability of phytictissue to redissolve iron ion in the brain tissue provides a way totreat age-related degenerative disease, such as Alzheimer's disease.

Example 4 Crystalline Property of the Phytic Citrate Compounds

Table 2 shows the crystalline property of phytic citrate, as opposed tophytic acid, calcium phytate, and calcium magnesium phytate:

TABLE 2 PROPERTIES OF PHYTIC CITRATE, PHYTIC ACID, Ca PHYTATE, Ca MgPHYTATE, AND Na PHYTATE Phytic Phytic Ca- CaMg- Citrate Acid PhytatePhytate Appearance White crystalline Slight yellow white white powderviscous liquid powder powder Solubility Very soluble N/A Easily solubleVery soluble in water in acid but in acid but insoluble insoluble inwater in water Heavy metals max 0.0013% max 0.0025% max 0.005% max0.005% (as Pb) Arsenic max 0.0002% max 0.0003% max 0.0005% max. 0.0005%sulfate max. 0.007% max. 0.071% ND* ND* ND*: Not determined

The results as shown in Table 2 demonstrate that phytic citrate (phytichexa-citrate) was in crystalline form. It was extremely soluble inwater, and it contained very low amounts of heavy metals (lead), arsenicand sulfate. These results support the notion that phytic citrate waseasy to be dissolved, and contained low toxic substances, so that itcould be used safely by humans.

Example 5 Biodegradability of Phytic Citrate

The biodegradability of phytic citrate was evaluated according to themethod of “301 A DOC Die-Away Test” (1993), OECDGuidelines for Testingof Chemicals. The results from degradation at both 7 and 14 days wereshown in Table 3.

TABLE 3 BIODEGRADABILITY OF PHYTIC CITRATE Test Flask Degradation (%) indays Test suspension 7 14 14 (mean) 1 >90 (98.0) >90 (98.6) >90 (99.5)2 >90 (97.6) >90 (100)  3 >90 (99.4) >90 (100)  Abiotic sterile control<10 <10 — Absorption <10 <10 — Aniline Reference >90 (100)  >90 (99.7) —

The results as shown in Table 3 demonstrate that phytic citrate wasreadily biodegradable so that it was safe to be used in humans.

CONCLUSION

The phytic citrate compound of the present invention evolves withseveral characteristics of both citric acid and phytic acid, which areboth considered to be very beneficial additives in the diet of humanbeings, and non-toxic. Thus, the phytic citrate compounds not onlydemonstrated a superior chelating effects than EDTA (as shown in Table1), but also were non-toxic (as shown in Table 2), and could bebiodegradable (as shown in Table 3) so that it was superior to EDTA,which has shown toxic and carcinogenic characteristics.

Additionally, since citrate is combined with phytic acid at the carbonoxygen bond on each of the carbon atoms of the aromatic ring, the bondsbetween the oxygen atom of phytic acid and the citrate complex form verystrong covalent bonds that help prevent instability of the molecule.Further, the phytic citrate compounds are very soluble despite its highmolecular weight (as demonstrated in Table 2). Due to its numeroushydroxyl groups, the phytic citrate compound is an extremely polarmolecule that far exceeds the solubility and chelation properties ofother conventional chelators, such as inositol, phytic acid, and citricacid.

One primary use of the phytic citrate compound is to act as an arteryplaque dissolver, due to its superior metals dissolution/chelation rate(as shown in FIG. 2). As many are aware, blood acts as a concentratedsaline solution containing both dissolved and suspended solids thatrapidly circulate through the arteries and the arterioles. Dissolvedsolids in the blood include nutrients absorbed from the colon and/orintestinal track. Suspended solids include platelets, red blood cellsand white blood cells. Over time, some dissolved solids form solidprecipitates that adhere to the inner walls of the circulatory systemforming solid arterial plaque, which can lead to severe blockage inmajor blood vessels. However, due to the many chemical properties of thephytic citrate compound, it is particularly successful in strippingplaque from arteries and arterioles. For example, the phytic citratecompound is a highly soluble molecule with both hydrophobic andhydrophilic properties. Such a characteristic allows the phytic citratecompound to remain dissolved in water due to its hydrophilic properties,while also allowing it to attach or adhere itself to solids that itcomes into contact with as a result of its hydrophobic properties. Assuch, the phytic citrate compound acts similarly to a surfactantallowing it to act as a removal agent of plaque from arteries andarterioles, while it rapidly flows through the cardiovascular system.

Additionally, the phytic citrate compound has very powerful chelationcharacteristics that re-dissolve the precipitated solids. Thesere-dissolved materials are maintained in their soluble form until theyare eventually excreted through the renal system. As demonstrated inFIG. 2, the phytic citrate compounds were especially effective inre-dissolving iron ions in brain tissue, which could be used fortreating patients with degenerative disease, such as Alzheimer'sdisease.

Finally, the phytic citrate compound has several novel and significantdifferences from the conventional chelators. First, the chemicalcompound has a rapid dissolution constant, which allows it to dissolverapidly and readily. Due to this enhanced chelating capacity, thebonding of metals and metalloids with the conjugate product produces asoluble ionic product that maintains its soluble form in highconcentrations in the saline solution of blood. As such, the chemicalcompound at very low concentrations has the ability to dissolve arteryplaque for treatment of arteriosclerosis, as well as the ability toremove copper, zinc, and iron deposits in the brain tissue for treatmentof Alzheimer's disease and other age-related degenerative disorders.

While the above description contains many specificities, these shouldnot be construed as limitations on the scope of the invention, but asexemplifications of the presently preferred embodiments thereof. Manyother ramifications and variations are possible within the teachings ofthe invention. Thus, the scope of the invention should be determined bythe appended claims and their legal equivalents, and not by the examplesgiven.

1-18. (canceled)
 19. A method of removing artery plaque comprising:administering a chemical compound or a salt thereof; wherein saidchemical compound is represented by the following formula:

wherein R is H, or citrate; and wherein at least one R is citrate. 20.The method of claim 1 wherein said salt of said chemical compoundcontains an ion selected from the group consisting of Na⁺, K⁺, Ca²⁺, andMg²⁺.
 21. The method of claim 1, wherein said chemical compound is incrystalline form.
 22. The method of claim 1, wherein said chemicalcompound is administered in an aqueous solution.
 23. A method oftreating an age-related degenerative disorder in a host comprising:administering a chemical compound or a salt thereof; wherein saidchemical compound is represented by the following formula:

wherein R is H, or citrate; and wherein at least one R is citrate. 24.The method of claim 5, wherein said salt of said chemical compoundcontains an ion selected from the group consisting of Na⁺, K⁺, Ca²⁺, andMg²⁺.
 25. The method of claim 5, wherein said chemical compound is incrystalline form.
 26. The method of claim 5, wherein said chemicalcompound is administered in an aqueous solution.
 27. The method of claim5, wherein said age-related degenerative disorder is Alzheimer'sdisease.